PREFACE
This document is a protocol template for clinical studies that pose greater than minimal risk to
study subjects and will require review by the full IRB. Minimal risk is defined by 45 U.S. Code of
Federal Regulations (CFR) 46.102 (i) as follows:
“Minimal risk means that the probability and magnitude of harm or discomfort
anticipated in the research are not greater in and of themselves than those ordinarily
encountered in daily life or during the performance of routine physical or psychological
examinations or tests.”
Refer to: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.102
Note that instructions and explanatory text are indicated by italics and should be replaced in
your protocol document with appropriate protocol-specific text. Section headings and template
text formatted in regular type should be included in your protocol document as provided in the
template.
Throughout this protocol template, there may be subject headings that do not apply to your
particular study. In such instances, please write “not applicable.”
In places where the information is duplicative, it is acceptable to reference another section
rather that repeating the information.
After the sections in this template has been answered, you will need to update the Table of
Contents for this document. Consult with computer support within your department for
assistance.
____________________________________________________________________________________________
TITLE
Protocol Number:
Protocol number required.
Sponsored by:
Principal Investigator:
Medical Monitor: If applicable
Draft or Version Number:
Month, Day, Year
This template is adapted from the ICH guidance document E6 (Good Clinical Practices), Section 6.
____________________________________________________________________________________________
Statement of Compliance
Provide a statement that the trial will be conducted in compliance with the protocol, International
Conference on Harmonization Good Clinical Practice (ICH GCP) and the applicable regulatory
requirements. An example is provided below:
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the
following [use applicable regulations depending on study location and sponsor requirements;
samples follow]:

U.S. Code of Federal Regulations applicable to clinical studies (45 CFR 46)

ICH GCP E6

Completion of Human Subjects Protection Training
Refer to: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.
http://www.fda.gov/cder/guidance/959fnl.pdf
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-061.html
http://cme.cancer.gov/c01/
____________________________________________________________________________________________
i
SIGNATURE PAGE
The signature below constitutes the approval of this protocol and the attachments, and provides
the necessary assurances that this trial will be conducted according to all stipulations of the
protocol, including all statements regarding confidentiality, and according to local legal and
regulatory requirements and applicable US federal regulations and ICH guidelines.
Principal Investigator
Signed:
Name
Title
Date:
____________________________________________________________________________________________
ii
Table of Contents
page
Statement of Compliance ................................................................................................................. i
Signature Page ................................................................................................................................ ii
List of Abbreviations ........................................................................................................................ v
Protocol Summary .......................................................................................................................... vi
1
2
3
4
5
6
7
8
Key Roles ............................................................................................................................... 1
Background Information and Scientific Rationale ................................................................. 2
2.1
Background Information ............................................................................................. 2
2.2
Rationale .................................................................................................................... 2
2.3
Potential Risks and Benefits ...................................................................................... 2
2.3.1 Potential Risks ............................................................................................... 2
2.3.2 Known Potential Benefits ............................................................................... 3
Objectives .............................................................................................................................. 4
Study Design .......................................................................................................................... 5
4.1
Selection of the Study Population.............................................................................. 5
4.2
Inclusion/Exclusion Criteria ....................................................................................... 6
Study Procedures/Evaluations .............................................................................................. 7
5.1
Study Procedures ...................................................................................................... 7
5.2
Laboratory Evaluations .............................................................................................. 7
5.2.1 Laboratory Evaluations/Assays ..................................................................... 7
5.2.2 Special Assays or Procedures ....................................................................... 7
5.2.3 Specimen Collection, Preparation, Handling and Shipping .......................... 8
5.3
Subject Compensation ............................................................................................... 8
Study Schedule ...................................................................................................................... 9
6.1
Screening ................................................................................................................... 9
6.2
Enrollment/Baseline, if applicable ............................................................................. 9
6.3
Follow-up and Final Visits, if applicable .................................................................... 9
6.4
Early Termination Visit, if applicable ......................................................................... 9
6.5
Criteria for Discontinuation or Withdrawal of a Subject (or a Cohort), if applicable 10
Assessment of Outcome Measures .................................................................................... 11
7.1
Specification of the Appropriate Outcome Measures.............................................. 11
7.1.1 Primary Outcome Measures ........................................................................ 11
7.1.2 Secondary Outcome Measures ................................................................... 11
Safety assessment and reporting ........................................................................................ 12
8.1
Definition of Adverse Event (AE) ............................................................................. 12
8.2
Definition of Serious Adverse Event (SAE) ............................................................. 12
8.3
Reporting Procedures .............................................................................................. 13
8.3.1 Serious Adverse Event Detection and Reporting ........................................ 13
8.3.2 Reporting of Pregnancy ............................................................................... 14
8.3.3 Procedures to be Followed in the Event of Abnormal Laboratory Test
Values or Abnormal Clinical Findings .......................................................... 14
____________________________________________________________________________________________
iii
Table of Contents - continued
page
8.3.4 Type and Duration of the Follow-up of Subjects After Adverse Events ...... 14
8.4
Halting Rules ............................................................................................................ 14
9
Clinical Monitoring Structure ................................................................................................ 16
9.1
Site Monitoring Plan ................................................................................................. 16
10 Statistical Considerations .................................................................................................... 17
10.1 Study Outcome Measures ....................................................................................... 17
10.2 Sample Size Considerations ................................................................................... 17
10.3 Participant Enrollment and Follow-Up ..................................................................... 17
10.4 Analysis Plan............................................................................................................ 17
11 Access to Source Data/Documents ..................................................................................... 19
12 Quality Control and Quality Assurance ............................................................................... 20
13 Ethics/Protection of Human Subjects .................................................................................. 21
13.1 Declaration of Helsinki ............................................................................................. 21
13.2 Institutional Review Board ....................................................................................... 21
13.3 Informed Consent Process ...................................................................................... 21
13.3.1 Informed Consent/Assent Process (in Case of a Minor or others unable to
consent for themselves) ............................................................................... 23
13.4 Exclusion of Women, Minorities, and Children (Special Populations) .................... 23
13.5 Subject Confidentiality ............................................................................................. 23
13.6 Future Use of Stored Specimens ............................................................................ 24
14 Data Handling and Record Keeping .................................................................................... 25
14.1 Data Management Responsibilities ......................................................................... 25
14.2 Data Capture Methods ............................................................................................. 26
14.3 Types of Data ........................................................................................................... 26
14.4 Timing/Reports ......................................................................................................... 26
14.5 Study Records Retention ......................................................................................... 26
14.6 Protocol Deviations .................................................................................................. 26
15 Publication Policy ................................................................................................................. 27
16 Literature References .......................................................................................................... 28
EXAMPLE: Data and Safety Monitoring Plan ................................................................................ 32
SUPPLEMENTS/APPENDICES
A: Study Schedule
____________________________________________________________________________________________
iv
____________________________________________________________________________________________
List of Abbreviations
AE
CFR
CRF
DSMB
FDA
FWA
GCP
ICF
ICH
IRB
JAMA
MOP
N
NEJM
NIH
OHRP
PI
SAE
Adverse Event
Code of Federal Regulations
Case Report Form
Data and Safety Monitoring Board
Food and Drug Administration
Federal-Wide Assurance
Good Clinical Practice
Informed Consent Form
International Conference on Harmonisation
Institutional Review Board
Journal of the American Medical Association
Manual of Procedures
Number (typically refers to subjects)
New England Journal of Medicine
National Institutes of Health
Office for Human Research Protections
Principal Investigator
Serious Adverse Event
This list should be expanded to include protocol-specific terms.
____________________________________________________________________________________________
v
Protocol Summary
Limit to 1-2 pages
Title:
Population:
Include sample size, gender, age, general health status, geographic
location
Number of Sites:
3 or fewer, list here; otherwise, list only in an Appendix and in Section 1
Study Duration:
State duration of study
Subject Duration:
State duration per subject
Objectives:
Include primary/secondary outcome measures and method by which outcome will be
determined; copy objectives and clinical/laboratory outcome measures from the appropriate
sections of the protocol. Include a sentence or two about efficacy and safety assessments.
Primary:

Secondary:

Schematic of Study Design:
Optional
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vi
Example: Flow diagram
Prior to
Enrollment
Total N: Obtain informed consent. Screen subjects by criteria; obtain history document.
Study Procedure, Intervention, or Specimen Collection
Study Visit 1
Study Visit 2
Assessment
Etc.
Assessment of Final Study
Outcome Measures
____________________________________________________________________________________________
vii
1
KEY ROLES
See ICH E6 GCP, Section 6.1
(http://www.fda.gov/cder/guidance/959fnl.pdf).
Individuals:
Principal Investigator:
Medical Monitor: (if applicable)
Provide the following information:
Name, degree, title
Institution
Address
Phone Number
Fax Number
E-mail
Institutions: Study sites, Clinical laboratory (ies) and other medical or technical departments
and/or institutions, as applicable.
Provide the following information for each organization or institution:
Institution
Address
Contact Person
Phone Number
Fax Number
E-mail
Optional:
Consider listing, for example
Major International Collaborators, if not included as site investigators
Protocol Data Manager, Epidemiologist, Statistician
Industry Representative(s)
Other individuals should be listed in a separate document (e.g., the Manual of
Procedures) as appropriate
____________________________________________________________________________________________
1
2
BACKGROUND INFORMATION AND SCIENTIFIC
RATIONALE
2.1
Background Information
See ICH E6 GCP, Section 6.2 (http://www.fda.gov/cder/guidance/959fnl.pdf).
Include:

Hypothesis of study

A summary of findings from studies that have potential significance to proposed study

Discussion of important literature and data that are relevant to the study and that provide
background for the study (reference citations in Reference section)

Applicable clinical, epidemiological or public health background or context of the study
2.2
Rationale
Include a description of and justification for selection of study population.
2.3
Potential Risks and Benefits
Include a discussion of known risks and benefits, if any, to human subjects.
Refer to 45 CFR Part 46.116 (a) (2) and (3).
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.116
2.3.1 Potential Risks
Describe in detail any physical, psychological, social, legal, economic or any other risks
to subjects that the PI foresees, as to each of the following:

Immediate risks

Long range risks

Rationale for the necessity of such risks
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2

Alternative data gathering procedures that have been considered or will be
considered

Why alternative procedures may not be feasible

Why the value of the information to be gained outweighs the risks involved.
2.3.2 Known Potential Benefits
If the research is beneficial (i.e., the subject derives a direct benefit of either money or
treatment from participating in the study), describe in detail any physical, psychological,
social, legal, economic or any other benefits to subjects that the PI foresees, as to each
of the following:
____________________________________________________________________________________________
3
3
OBJECTIVES
A detailed description of the objectives of the study is included in this section. These typically
include:

Statement of purpose e.g., to assess, to determine, to compare, to evaluate

Method of assessing how the objective is met, i.e., the study outcome measures
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4
STUDY DESIGN
4
See ICH E6 GCP, Section 6.4
(http://www.fda.gov/cder/guidance/959fnl.pdf).
The scientific integrity of the study and the credibility of the data from the study depend
substantially on the study design. A description of the study design should include:

A description of the design of the study to be conducted, including controls

Approximate time to obtain specimens

Expected duration of subject participation

Description of subject participation (e.g., number of times and the frequency at which a
subject will provide specimens)

Methods for collecting specimens and data.

A specific statement of the primary and secondary outcomes to be measured during the
study (must be consistent with Study Objectives, as stated in Section 3)

Identify structure for safety oversight (e.g., DSMB, Study Population)
4.1
Selection of the Study Population
If the study intends to enroll children, pregnant women, prisoners, or other vulnerable
populations, see applicable section of 45 CFR 46 Subpart B – Additional DHHS Protections
Pertaining to Research, Development and Related Activities Involving Fetuses, Pregnant
Women, and Human In Vitro Fertilization (45 CFR 46.201-46.211); Subpart C – Additional
DHHS Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as
Subjects (45 CFR 46.301-46.306); Subpart D – Additional DHHS Protections in Children
Involved as Subjects in Research (45 CFR 46.401-409). Please refer to these guidelines when
choosing the study population.
Refer to: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.

Provide the target sample size, including actual numbers to be enrolled.

Include numbers of women, minorities and children expected to be recruited. If women,
minorities and children will not be recruited, explain why not. Provide justification for
Exclusion in Ethics/Protection of Human Subjects, Section 14.4. Refer to:
http://grants2.nih.gov/grants/funding/women_min/women_min.htm

Indicate from where the study population will be drawn (e.g., inpatient hospital setting,
outpatient clinics, student health service). Where appropriate (single center studies),
include names of hospitals, clinics, etc.
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5

Identify strategies for subject recruitment and retention.

If subjects require screening: distinguish between screening subjects (e.g., discussing the
study with them) vs. enrolling subjects (e.g., obtaining informed consent and obtaining
samples). Note: if screening procedures are required for eligibility (e.g., laboratory tests),
there must be a separate screening consent form in addition to the informed consent form
for study participation.
Eligibility Criteria

The eligibility criteria should provide a definition of subject characteristics required for study
entry.

The same criterion should not be listed as both an inclusion and exclusion criterion (e.g., do
not state age >32 years old as an inclusion criterion and also age ≤32 years old as an
exclusion criterion).

Select screening laboratory tests carefully, if they will be used.
4.2
Inclusion/Exclusion Criteria
Provide a statement that subject must meet all of the inclusion criteria to participate in this study
and then list each criterion.
Examples include the following: informed consent obtained and signed, age, presence or
absence of a medical condition/disease, required laboratory result, understanding of study
procedures, ability to comply with study procedures for the entire length of the study.
Provide a statement that all subjects meeting any of the exclusion criteria at baseline will be
excluded from study participation and then list each criterion.
Examples include the following: medical condition or laboratory finding that precludes
participation, recent (with time frame) febrile illness that precludes participation, pregnancy or
breast feeding.
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6
STUDY PROCEDURES/EVALUATIONS
5
Information outlined in the Procedures/Evaluations section should refer to and be consistent
with the information in the Schedule of Procedures/Evaluations in Appendix A.
5.1
Study Procedures
Specify the type of information that will be gathered, along with the means for collecting and
recording data.
List all relevant clinical evaluations to be done during the protocol, if any, and provide details of
what are included and special instructions.
Examples:

Specimen collection

Medical history

Concomitant medications

Physical exam

Counseling procedures.
5.2
Laboratory Evaluations
5.2.1 Laboratory Evaluations/Assays
List all laboratory evaluations, if applicable. Include specific test components and
estimated volume and type of specimens needed for each test. Specify laboratory
methods (e.g., use consistent laboratory method throughout study). Provide descriptions
of assays to be performed.
5.2.2 Special Assays or Procedures
List special assays or procedures required to assess the study product (e.g.,
immunology assays, PK studies, photographs). For laboratory assays, include specific
assays, estimated volume and type of specimen needed for each test. For procedures,
provide special instructions or precautions. If more than one laboratory will be used,
specify which assays or evaluations will be done by each laboratory.
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7
5.2.3 Specimen Collection, Preparation, Handling and Shipping
5.2.3.1
Instructions for Specimen Preparation, Handling, and Storage
Special instructions for the collection, labeling, preparation, handling, and storage of
specimens should be summarized in this section and clearly detailed in a Manual of
Procedures. These instructions include required temperatures, aliquots of specimens,
whether samples will be frozen, where they will be stored, how they will be labeled, etc.
Include a discussion of long-term access and consent for future use. There may need to
be additional considerations for biological specimens, especially biohazardous
specimens that require special containment.
5.2.3.2
Specimen Shipment
State the frequency with which specimens are to be shipped and to what address.
Include contact information for laboratory personnel. Include days and times shipments
are allowed and any labeling requirements for specimen shipping. Also, any special
instructions such as dry ice or wet ice or the completion of a specimen-tracking log are
included. Place specific details in a Manual of Procedures and reference within the
protocol.
5.3
Subject Compensation
Provide information regarding any compensation and/or reimbursement which will be provided.
What is the difference between compensation and reimbursement?
A reimbursement is used when the subject is paid back for travel expenses such as mileage,
lodging, food while traveling. Receipts or mileage must be submitted for a reimbursement.
Compensation is "payment" for things such as time, discomfort, inconvenience.
Total possible compensation should reflect the true value of the total possible dollar amount per
participant for one year involvement in the study whether it be cash, check, gift card, goods, etc.
or a combination of these items.
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8
6
STUDY SCHEDULE
Information outlined in the Study Schedule section should refer to and be consistent with the
information in the Schedule of Procedures/Evaluations in Appendix A and in Section 6.
The evaluations to be done must be listed individually in this section or alternatively, refer to the
Schedule of Procedures/Evaluations (Appendix A).
Allowable windows should be stated for all visits.
6.1
Screening
This section must include instructions for obtaining signed informed consent.
Following consent, include only those evaluations necessary to assess whether a subject meets
enrollment criteria. Discuss the sequence of events that should occur during screening and
decision points regarding eligibility. List the timeframe prior to enrollment within which
screening tests and evaluations must be done (e.g., within 28 days prior to enrollment).
6.2
Enrollment/Baseline, if applicable
If applicable, include discussion of evaluations/procedures necessary to assess or confirm
whether a subject still meets the eligibility criteria and may be enrolled.
6.3
Follow-up and Final Visits, if applicable
Include discussion of evaluations/procedures. Discuss the sequence of events that should occur
during the visit, if applicable. Include, as applicable, counseling, medications, adverse events,
etc. Define when the final study visit should occur and any special evaluations or instructions to
the subject.
6.4
Early Termination Visit, if applicable
Specify which of the evaluations required for the final study visit should be done at a termination
visit if early termination occurs and if the participant is willing. Subjects may withdraw voluntarily
from participation in the study at any time.
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9
6.5
Criteria for Discontinuation or Withdrawal of a Subject (or a
Cohort), if applicable
List possible reasons for discontinuation of a subject in this section (e.g., development of
laboratory toxicities, study closure due to DSMB review).
____________________________________________________________________________________________
10
7
ASSESSMENT OF OUTCOME MEASURES
Refer to ICH E6 GCP, Sections 6.7-6.8
(http://www.fda.gov/cder/guidance/959fnl.pdf).
7.1
Specification of the Appropriate Outcome Measures
7.1.1 Primary Outcome Measures
7.1.2 Secondary Outcome Measures
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11
SAFETY ASSESSMENT AND REPORTING
8
Describe how any adverse events resulting from study procedures will be captured and
reported. Describe time frame for reporting and collecting AEs and SAEs.
8.1
Definition of Adverse Event (AE)
See ICH E6 GCP, Section 1.2
(http://www.fda.gov/cder/guidance/959fnl.pdf)
An AE is any untoward medical occurrence in a subject undergoing a study related procedure
and believed reasonably to be caused that study related procedure. Include time period of
collection.
8.2
Definition of Serious Adverse Event (SAE)
See ICH E6 GCP, Section 1.50
(http://www.fda.gov/cder/guidance/959fnl.pdf).
An SAE is any untoward medical occurrence that:

Results in death.

Is life-threatening. Any adverse experience that places the subject, in the view of the
investigator, at immediate risk of death from the reaction as it occurred (i.e., it does not
include a reaction that, had it occurred in a more serious form, might have caused death).

Requires in-patient hospitalization or prolongation of existing hospitalization.

Results in persistent or significant disability or incapacity.

Is a congenital anomaly/birth defect.

An event that required intervention to prevent permanent impairment or damage.

Important medical events that do not result in death, are not life-threatening, or do not
require hospitalization may be considered serious adverse events when, based upon
appropriate medical judgment, they might jeopardize the subject and might require medical
or surgical intervention to prevent one of the outcomes listed above.

In addition, protocols may specify other events that require reporting as SAEs (e.g., HIV
infection, pregnancy). Include time period of collection.
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12
8.3
Reporting Procedures
Note: All studies which are greater than minimal risk must have an AE reporting system
in place.
Include details of the protocol-specific reporting procedures, including the individual responsible
for each step (e.g., the Investigator, the Medical Monitor), how decisions will be made regarding
determining relatedness and grading severity, which forms should be completed, how reports
will be distributed and what follow-up is required.
Include specific details of reporting procedures for:

Deaths and life-threatening events

Other SAEs

Other adverse events
Subsequent review of serious, unexpected and related adverse events by the Medical Monitor,
Safety Monitoring Committee, ethics review committee or IRB, the sponsor(s), or the FDA or
relevant local regulatory authorities may also result in suspension of the trial.
8.3.1 Serious Adverse Event Detection and Reporting
Example text:
“For those events meeting the previously described definition of Serious Adverse
Events, the completion of a Serious Adverse Event report form is required. Specific
information on where to send this form is included in the Manual of Procedures for this
study.
All serious adverse events will be recorded on the appropriate serious adverse event
case report form, followed through resolution by a study physician, and reviewed by a
study physician.
All deaths, whether associated or not associated, will be recorded on the Serious Event
Form and sent by fax within 24 hours of site awareness of the death.

Serious adverse events other than death, regardless of relationship, will be
reported via fax by the site within 72 hours of becoming aware of the event.
Other supporting documentation of the event may be requested by the pharmacovigilance
contractor and should be provided as soon as possible. All SAEs will be followed until
satisfactory resolution or until the Principal Investigator or Subinvestigator deems the event
to be chronic or the patient to be stable.
ICH GCP 6, Section 4.11 require that an investigator notifies the sponsor, regulatory
authority(ies) and the local IRB immediately of any serious adverse event, deaths, or life____________________________________________________________________________________________
13
threatening problems that occur in the study. Adverse events and/or laboratory
abnormalities identified in the protocol as critical to safety evaluations should be reported
in accordance with reporting requirements specified in the protocol. “
8.3.2 Reporting of Pregnancy
State the study’s pregnancy-related policy and procedure. Include appropriate
mechanisms for reporting to sponsor, study leadership, IRB, and regulatory agencies.
Provide appropriate modifications to study procedures.
8.3.3 Procedures to be Followed in the Event of Abnormal Laboratory Test
Values or Abnormal Clinical Findings
Collection of laboratory data should be limited to those laboratory parameters that are
relevant to safety, study outcome measures and/or clinical outcome.
The Toxicity Tables will define what values or findings are considered abnormal.
Reporting will be dependent on the abnormality, the study intervention and the study
population, but should be stated specifically. Consider the context of the study and
adjust reporting procedures appropriately for the study population.
Define the circumstances in which abnormal laboratory values will be reported as
AEs/SAEs. Generally, in healthy people, a Grade 3 abnormality is an SAE. In sick
populations, define in terms of a change from baseline and disease progression.
8.3.4 Type and Duration of the Follow-up of Subjects After Adverse Events
See ICH GCP 6, Section 6.8
(http://www.fda.gov/cder/guidance/959fnl.pdf).
Describe how adverse events will be followed until resolved or considered stable.
Specify procedures for reporting and follow-up of AEs that are consistent with the
Schedule of Procedures/Evaluations.
8.4
Halting Rules
Describe safety findings that would temporarily suspend enrollment and/or intervention until a
safety review is convened (either routine or ad hoc), the objective of which is a decision as to
whether the study should continue per protocol, proceed with caution, be further investigated,
be discontinued, or be modified and then proceed.
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14
Examples of findings that might trigger a safety review are the number of SAEs overall, the
number of occurrences of a particular type of SAE, severe AEs/reactions, or increased
frequency of events.
Subsequent review of serious, unexpected and related AEs by the Medical Monitor, DSMB,
ethics review committee or IRB, the sponsor(s), or the FDA or relevant local regulatory
authorities may suspend further study procedures at a site.
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15
9
CLINICAL MONITORING STRUCTURE
This section will describe the study monitoring to be conducted to ensure the safety and conduct
of the study complies with 45 CFR 46, GCP and ICH Guidelines, and other sponsor
collaborator’s guidelines, as appropriate.
See ICH E6 GCP, Section 5.18
(http://www.fda.gov/cder/guidance/959fnl.pdf).
Also refer to: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.
9.1
Site Monitoring Plan
Site monitoring is conducted to ensure the human subject protection, study procedures,
laboratory, and data collection processes are of high quality and meets sponsor, GCP/ICH and,
when appropriate, regulatory guidelines. This section will give a general description of how site
monitoring will be conducted.
The monitoring plan must include the number of subject charts to be reviewed, which/what
proportion of data fields and what will be monitored, and who will be responsible for conducting
the monitoring visits, and who will be responsible for ensuring that monitoring findings are
addressed.
This section is required if a UVa faculty member, employee is the overall PI of this study.
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16
10
STATISTICAL CONSIDERATIONS
10.1 Study Outcome Measures
Discuss how the outcome measures will be measured and transformed, if relevant, before
analysis (e.g., is the primary variable binary, categorical, or continuous?)
10.2 Sample Size Considerations
Provide information needed to validate your calculations, and also to judge the feasibility of
enrolling subjects and obtaining the necessary number of specimens.
In particular, specify all of the following:

Approach to handling withdrawals and protocol violations

Statistical method used to calculate the sample size, with a reference for it and for any
software utilized

Discuss any measures to decrease bias or increase precision in ascertainment of study
endpoints (e.g., blinding of laboratory staff, use of a central laboratory to perform assays).
Present calculations from a suitable range of assumptions to gauge the robustness of the
proposed sample size.
Discuss whether the sample size also provides sufficient power for addressing secondary
objectives, or for secondary analyses in key subgroup populations.
In some circumstances, exploratory or pilot studies may be planned for convenience of
obtaining samples.
10.3 Participant Enrollment and Follow-Up
Summarize the total number of enrollees and the total duration of accrual and retention
capabilities.
10.4 Analysis Plan
This section can be used to elaborate on primary analyses that underlie the sample size
calculation in Section 11.2 above and to describe secondary analyses for the primary or
____________________________________________________________________________________________
17
secondary objectives. Details must be provided in a separate statistical analysis plan written
later, but prior to interim or ad hoc analyses.
Plans must clearly identify the analyses cohorts, if applicable, and methods to account for
missing, unused or spurious data. If specialized statistical techniques (e.g., methods for
sequencing or microarray analysis) will be used, please discuss and indicate who will be
performing the analysis.
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18
11
ACCESS TO SOURCE DATA/DOCUMENTS
Each participating site will maintain appropriate medical and research records for this trial, in
compliance with Section 4.9 of ICH E6 GCP, and regulatory and institutional requirements for
the protection of confidentiality of subjects. As part of participating each site will permit
authorized representatives of the sponsor(s), and regulatory agencies to examine (and when
required by applicable law, to copy) clinical records for the purposes of quality assurance
reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other
activities in a study necessary for the reconstruction and evaluation of the trial. Examples of
these original documents and data records include, but are not limited to, hospital records,
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or
transcriptions certified after verification as being accurate and complete, microfiches,
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical
study.
Refer to: http://www.fda.gov/cder/guidance/959fnl.pdf.
____________________________________________________________________________________________
19
12
QUALITY CONTROL AND QUALITY ASSURANCE
This section will briefly indicate the plans for local quality control (QC). Data will be evaluated
for compliance with protocol and accuracy in relation to source documents. The study will be
conducted in accordance with procedures identified in the protocol. The types of materials to be
reviewed, who is responsible, and the schedule for reviews may be specified or referenced in
other documents. Types and mechanisms of training of staff for the study should be specified.
SOPs must be used at all clinical and laboratory sites. Regular monitoring and an independent
audit must be performed according to GCP/ICH (e.g., data monitoring).
Briefly describe methods (e.g., internal auditing) for assuring protocol compliance, ethical
standards, regulatory compliance, data quality and proper storage and handling of samples.
(Refer to ICH GCP E6, Section 5.1 http://www.fda.gov/cder/guidance/959fnl.pdf).
____________________________________________________________________________________________
20
13
ETHICS/PROTECTION OF HUMAN SUBJECTS
This section should include a description of the ethical considerations and context for the
conduct of the study.
13.1 Declaration of Helsinki
Include this section if applicable.
If the study is conducted at international sites, include a statement about compliance with the
Declaration of Helsinki.
Example text:
”The investigator will ensure that this study is conducted in full conformity with the
current revision of the Declaration of Helsinki, or with the International Conference for
Harmonisation Good Clinical Practice (ICH-GCP) regulations and guidelines, whichever
affords the greater protection to the subject.”
13.2 Institutional Review Board
Each participating institution must provide for the review and approval of this protocol and the
associated informed consent documents and recruitment material by an appropriate
independent ethics review committee (IEC) or Institutional Review Board (IRB) registered with
OHRP. Any amendments to the protocol or consent materials must also be approved before
they are placed into use. In both the United States and in other countries, only institutions
holding a current U. S. Federal-Wide Assurance issued by OHRP may participate. Refer to:
http://ohrp.osophs.dhhs.gov.
13.3 Informed Consent Process
Refer to ICH GCP E6, Section 4.8 (http://www.fda.gov/cder/guidance/959fnl.pdf).
Refer to FDA Regulations on Informed Consent 21 CFR Part 50 - Subpart B
(http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=50).
Refer to DHHS Regulation on Informed Consent 45 CFR Part 46 - Subpart A, 46.116
(http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.116).
____________________________________________________________________________________________
21
See also Tips on Informed Consents
(http://www.hhs.gov/ohrp/humansubjects/guidance/ictips.htm).
See also Informed Consent Checklist
(http://www.hhs.gov/ohrp/humansubjects/assurance/consentckls.htm)
Describe the procedures for obtaining and documenting informed consent of study subjects.
Make provisions for special populations, e.g., non-English speakers (refer to:
http://www.hhs.gov/ohrp/humansubjects/guidance/ic-non-e.htm), illiterate or non-writing
individuals, vulnerable populations.
Informed consent is required for all subjects, unless the requirement of informed consent is
specifically waived by the IRB. In obtaining and documenting informed consent, the investigator
should comply with applicable regulatory requirements and should adhere to GCP and to the
ethical principles that have their origin in the Declaration of Helsinki. Prior to the beginning of
the trial, the investigator should have the IRB written approval/favorable opinion of the written
informed consent form(s) and any other written information to be provided to the subjects.
Identify different consent forms that are needed for the study (e.g., screening, study
participation, HIV screening, future use specimens, plasmapheresis, assent form for minors).
Example text:
“Informed consent is a process that is initiated prior to the individual’s agreeing to
participate in the study and continuing throughout the individual’s study participation.
Extensive discussion of risks and possible benefits of participation in this study will be
provided to the subjects and their families. Consent forms describing in detail the study
procedures and risks are given to the subject and written documentation of informed
consent is required prior to enrolling in the study. Consent forms will be IRB approved
and the subject will be asked to read and review the document. Upon reviewing the
document, the investigator will explain the research study to the subject and answer any
questions that may arise. The subjects will sign the informed consent document prior to
being enrolled in the study. The subjects should have the opportunity to discuss the
study with their surrogates or think about it prior to agreeing to participate. The subjects
may withdraw consent at any time throughout the course of the study. A copy of the
informed consent document will be given to the subjects for their records. The rights
and welfare of the subjects will be protected by emphasizing to them that the quality of
their medical care will not be adversely affected if they decline to participate in this
study.”
Provide each institution with a sample consent form for subject participation. The consent form
should be separate from the protocol document.
____________________________________________________________________________________________
22
13.3.1 Informed Consent/Assent Process (in Case of a Minor or others
unable to consent for themselves)
Refer to ICH E6, Section 4.8.12
(http://www.fda.gov/cder/guidance/959fnl.pdf).
When a study includes subjects who may be enrolled in the study only with the consent
of the subject’s legally authorized representative (e.g., minors or subjects unable to
consent for themselves), the subject should be informed about the study to the extent
compatible with the subject’s understanding. If capable, the subject should assent and
sign and personally date the written consent form. A separate IRB-approved assent
form, describing (in simplified terms) the details of the study, study procedures and risks
may be used. Assent forms do not substitute for the consent form signed by the
subject’s legally acceptable representative. Consult with the institutions policies
regarding enrolling participants who are unable to provide informed consent for
themselves.
Subjects who are unable to give consent for themselves should not be enrolled in nontherapeutic research unless the objectives of the research cannot be met by enrolling
only persons who are able to give consent for their participation. The reviewing IRB
must give approval or a favorable opinion on their inclusion.
13.4 Exclusion of Women, Minorities, and Children (Special
Populations)
If the study intends to exclude any special populations, justify the exclusion of women,
minorities or children in the context of the study design.
13.5 Subject Confidentiality
Include procedures for maintaining subject confidentiality, any special data security
requirements, and record retention per the sponsor’s requirements.
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and the
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological
samples and genetic tests in addition to the clinical information relating to participating subjects.
The study protocol, documentation, data and all other information generated will be held in strict
confidence. No information concerning the study or the data will be released to any
unauthorized third party without prior written approval of the sponsor.
The study monitor or other authorized representatives of the sponsor may inspect all documents
and records required to be maintained by the Investigator, including but not limited to, medical
____________________________________________________________________________________________
23
records (office, clinic or hospital) and pharmacy records for the subjects in this study. The
clinical study site will permit access to such records.
13.6 Future Use of Stored Specimens
If residual specimens will be maintained after the study is complete, include the
provisions for consent and the options that are available for the volunteer to agree to the
future use of his/her specimens. Specify the location(s), if other than the clinical site,
where specimens will be maintained, if the site's IRB will review future studies, and
protections of confidentiality for any future studies with the stored specimens, e.g.,
specimens will be coded, bar-coded, de-linked. Include a statement that genetic testing
will not be performed if required by the IRB.
Refer to Human Research Regulation Chart 2 at:
http://www.hhs.gov/ohrp/humansubjects/guidance/decisioncharts.htm.
____________________________________________________________________________________________
24
14
DATA HANDLING AND RECORD KEEPING
Include instructions for special data handling or record keeping procedures required for
maintaining subject confidentiality, any special data security requirements, and record retention
per the sponsor’s requirements in this section.
Briefly describe steps to be taken to assure that the data collected are accurate, consistent,
complete and reliable and in accordance with ICH GCP guidelines and 21 CFR Part 11. The
description should include reference to source documentation, case report forms, instructions
for completing forms, data handling procedures, and procedures for data monitoring. Details
may be provided in a Manual of Procedures, User’s Guide or other citable reference document.
Refer to: http://www.fda.gov/ora/compliance_ref/part11/
14.1 Data Management Responsibilities
Describe responsibilities for data handling and record keeping as they specifically relate to the
sponsor, clinical site, laboratory, and data coordinating center. Information should include the
role in data collection, review of data, study materials, and reports, as well as retention of
source documents, files, and records. Describe coding dictionaries to be used and
reconciliation processes (if applicable).
All source documents and laboratory reports must be reviewed by the clinical team and data
entry staff, who will ensure that they are accurate and complete. Adverse Events must be
graded, assessed for severity and causality and reviewed by the site Principal Investigator or
designee.
Data collection is the responsibility of the study staff at the site under the supervision of the site
Principal Investigator. During the study, the Investigator must maintain complete and accurate
documentation for the study.
If data are to be generated in one location and transferred to another group, describe the
responsibilities of each party.
Indicate the roles of each party with regard to interpretation of data, plans for analysis, review of
tables and listings, and plans for reporting.
____________________________________________________________________________________________
25
14.2 Data Capture Methods
Provide details regarding the type of data capture that will be used for the study. Specify
whether it will be paper or electronic, distributed or central, batched or ongoing processing, and
any related requirements. Indicate expectations for time for submission of CRFs.
14.3 Types of Data
Indicate the types of data that will be collected.
14.4 Timing/Reports
Indicate the schedule for data review and reports. Specify whether reviews or reports are
ongoing, interim, or periodic. Identify plans for data analysis and submission of reports, steps for
freezing the data prior to analysis, and precautions related to blinded data. Indicate whether
and when coding is to occur.
14.5 Study Records Retention
Specify the length of time for the investigator to maintain all records pertaining to this study.
Indicate whether permission is required prior to destruction of records.
14.6 Protocol Deviations
Plans for detecting, reviewing and reporting deviations from the protocol should be described. A
statement may be included to indicate that exemptions for specific inclusion/exclusion
deviations are not allowed (if not handled separately in an investigator agreement) and/or
provisions for approval of inclusion/exclusion deviations can be described.
____________________________________________________________________________________________
26
15
PUBLICATION POLICY
If appropriate, the publication policy may be described in the study Manual of Procedures
(MOP).
The publication and authorship policies should be determined and clearly outlined in this
section. Refer to contract or clinical trials agreements. Policies regarding substudies should be
outlined in this section.
The following language may used in the protocol:
Following completion of the study, the investigator may publish the results of this research in a
scientific journal. The International Committee of Medical Journal Editors (ICMJE) member
journals have adopted a trials-registration policy as a condition for publication. This policy
requires that all clinical trials be registered in a public trials registry such as ClinicalTrials.gov,
which is sponsored by the National Library of Medicine. Other biomedical journals are
considering adopting similar policies. It is the responsibility of the sponsor to register this trial in
an acceptable registry. Any clinical trial starting enrollment after 01 July 2005 must be
registered either on or before the onset of patient enrollment. For trials that began enrollment
prior to this date, the ICMJE member journals will require registration by 13 September 2005
before considering the results of the trial for publication.
The ICMJE defines a clinical trial as any research project that prospectively assigns human
subjects to intervention or comparison groups to study the cause-and-effect relationship
between a medical intervention and a health outcome. Studies designed for other purposes,
such as to study pharmacokinetics or major toxicity (eg, Phase 1 trials), would be exempt from
this policy.
____________________________________________________________________________________________
27
16
LITERATURE REFERENCES
Include a list of relevant literature references in this section. Use a consistent, standard,
modern format, which might be dependent upon the required format for the anticipated journal
for publication (e.g., NEJM, JAMA). The preferred format is the Vancouver format, used in the
American Medical Association Manual of Style.
Examples:
Journal citation:
Davis JT, Allen HD, Powers JD, Cohen DM. Population requirements for capitation
planning in pediatric cardiac surgery. Arch Pediatr Adolesc Med. 1996;150(1):257-259.
Whole Book citation:
Sherlock S, Dooley J. Diseases of the Liver and Biliary System. 9th ed. Oxford, England:
Blackwell Scientific Publications; 1993.
Chapter in a Book citation:
Cole BR. Cystinosis and cystinuria. In: Jacobson HR, Striker GE, Klarh S, eds. The
Principles and Practice of Nephrology. Philadelphia, PA: BC Decker Inc.; 1991:396-403.
A full listing of Vancouver style guidelines can be found at:
International Committee of Medical Journal Editors. Uniform Requirements for Manuscripts
Submitted to Biomedical Journals. JAMA. 1997;277:927-934.
You may also refer to:
http://www.library.uwa.edu.au/guides/citingsources/vancouver.html
____________________________________________________________________________________________
28
SUPPLEMENTS/APPENDICES
Required Documents:
Provide with protocol:

Consent Form

Assent Form, if applicable

Future Use Consent, if applicable

Schedule of Events
Can be provided with the protocol or in separate documents

Manual of Procedures

Safety Monitoring Plan

Site Monitoring Plan

Copies of Case Report Form(s)
Additional/optional supplements:

Biosafety Precautions

Repository Instructions

Laboratory Handling

Site Roster
____________________________________________________________________________________________
29
Appendix A: Study Schedule
Time Point 4,
etc.
Study
Completion
Premature
Discontinuation
Time Point 3
Time Point 2
Time Point 1
Baseline
Screening
Follow-Up Schedule
X
X
X
X
X
Procedures
Signed Consent Form
X
X
Assessment of Eligibility Criteria
X
X
Review of Medical History
X
X
Review of Concomitant
Medications
X
X
Physical
Exam
Study Procedures
Complete
Clinical
Laboratory
Research
Laboratory
X
X
X
X
SymptomDirected
X
(X)
(X)
(X)
(X)
Vital Signs
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
X
X
Assessment of Adverse Events
Other
Procedures
X
Chemistry
X
X
(X)
(X)
(X)
(X)
X
X
Hematology
X
X
(X)
(X)
(X)
(X)
X
X
Urinalysis
X
X
(X)
(X)
(X)
(X)
X
X
Immunology
__mL whole
blood
X
(X)
(X)
X
X
(X)
(X)
(X)
(X)
(X)
(X) – As indicated/appropriate.
Provide a list of tests to be done, e.g.:
Hematology – Hemoglobin, hematocrit, WBC and differential count, platelet count
Biochemistry – Sodium, potassium, chloride, urea, creatinine, glucose, uric acid, bicarbonate, amylase, lipase, albumin, total
bilirubin, cholesterol, triglycerides, and CPK, as appropriate for the study. These are examples, specify list of tests.
Urinalysis – Protein and glucose, as appropriate for the study
Immunology – Specify specimen types for non-standard laboratory assays
Other – Other procedures that are done to evaluate outcome measures (e.g., photographs, X-rays)
Intervention – Modify as appropriate if intervention is administered more than once throughout the study
Specify time points for follow-up in days, weeks, or months, as appropriate for protocol.
At baseline, all procedures should be done before intervention.
Indicate volume of blood if frequent or large phlebotomies are part of the protocol over two months.
____________________________________________________________________________________________
30
____________________________________________________________________________________________
31
EXAMPLE: DATA AND SAFETY MONITORING PLAN
1. Definition:
1.1 How will you define adverse events (AE)) for this study?
An adverse event will be considered any undesirable sign, symptom or medical or
psychological condition even if the event is not considered to be related to the
investigational drug/device/intervention. Medical condition/diseases present before
starting the investigational drug/intervention will be considered adverse events only if
they worsen after starting study treatment/intervention. An adverse event is also any
undesirable and unintended effect of research occurring in human subjects as a
result of the collection of identifiable private information under the research. Adverse
events also include any problems associated with the use of an investigational
device that adversely affects the rights, safety or welfare of subjects.
1.2 How will you define serious adverse events?
A serious adverse event will be considered any undesirable sign, symptom, or
medical condition which is fatal, is life-threatening, requires or prolongs inpatient
hospitalization, results in persistent or significant disability/incapacity, constitutes
a congenital anomaly or birth defect, is medically significant and which the
investigator regards as serious based on appropriate medical judgment. An
important medical event is any AE that may not result in death, be lifethreatening, or require hospitalization but may be considered an SAE when,
based upon appropriate medical judgment, it may jeopardize the patient and may
require medical or surgical intervention to prevent one of the outcomes listed in
the definitions of SAEs.
1.3 What is the definition of an unanticipated problem?
An unanticipated problem is any event, experience that meets ALL 3 criteria below:
 Is unexpected in terms of nature, severity or frequency given the research
procedures that are described in the protocol-related documents AND in the
characteristics of the subject population being studies
 Related or possibly related to participation in research. This means that there
is a reasonable possibility that the incident may have been caused by the
procedures involved in the research study.
 The incident suggests that the research placed the subject or others at
greater risk of harm than was previously known or recognized OR results in
actual harm to the subject or others
1.4 What is the definition of a protocol violation?
A protocol violation is defined as any change, deviation, or departure from the study
design or procedures of a research project that is NOT approved by the IRB-HSR
prior to its initiation or implementation, OR deviation from standard operating
procedures, Good Clinical Practices (GCPs), federal, state or local regulations.
____________________________________________________________________________________________
32
Protocol violations may or may not be under the control of the study team or UVa
staff. These protocol violations may be major or minor violations.
1.5 If pregnancy occurs how will this information be managed?
_____ Adverse Event- will follow adverse event recording and reporting procedures
outlined in section 3.
_____ Unanticipated Problems- will follow Unanticipated Problem recording and
reporting procedures outlined in section 3.
_____ Other
2. Identified risks and plans to minimize risk
2.1 What risks are expected due to the intervention in this protocol?
Expected: is identified in nature, severity or frequency in the study documentation (protocol,
consent, Investigator Brochure, package insert etc) is considered an expected.




The risks should be consistent with those in the consent form and the investigator’s brochure
(if applicable), although they should be written in technical terms in the protocol and in lay
terminology in the consent form.
Separate risks by source of risk: (example: Risk of Radiation, Risk of Study Drug, Risk
of investigational device, etc.) If there is more than one source of risk- insert a separate
table for each risk.
If the study involves a removable device- include the potential risk from device removal
List the most serious risk first.
Expected Risks related to study
participation.
List the risks below
Add additional rows if needed
Delete this row if this protocol does
not represent reproductive risks.
Frequency
Check one frequency from each box below
____Occurs frequently
____Occurs infrequently
____Occurs rarely
____Frequency unknown
Minimized due to the requirements of this
protocol.
Reproductive Risks
Specify potential reproductive risks
Violation of subject’s privacy and
confidentiality
Minimized due to the requirements of the
privacy plan in this protocol
____________________________________________________________________________________________
33
Delete this row if this protocol does
not include Genetic Research
Risk of Genetic Research
See Genetic Research Section for
Risks
NA
2.2 List by bullet format a summary of safety tests/procedures/observations to be
performed.
Particularly list those tests or procedures that screen out ineligible research subjects and those that
monitor toxicity and other adverse outcomes. For example: Adequate screening, pregnancy testing, AE
monitoring at each visit, etc.)
2.3 Under what criteria would an INDIVIDUAL SUBJECT’S study treatment or study
participation be stopped or modified
_____At subject, PI or sponsor’s request
_____Treatment would be stopped if the subject had a serious adverse event
deemed related to study, or study drug will be increased if the subject tolerates
dosing insert details:_
2.4 Under what criteria would THE ENTIRE STUDY need to be stopped.
These are called stopping rules for early termination of the entire study.
List criteria regardless of whether the study is sponsored or not.
Be sure to include any criteria for which the UVa PI would halt the study at UVa.
Check all that apply
_____Per IRB, PI, DSMB, or sponsor discretion
_____Other: specify
2.5 What are the criteria for breaking the blind/mask?
_____NA – Not blinded/masked
_____Other: specify
2.6 How will subject withdrawals/dropouts be reported to the IRB prior to study
completion?
_____Continuation status report
_____Other: describe
____________________________________________________________________________________________
34
3. Adverse Event / Unanticipated Problem Recording and Reporting
3.1 Will all adverse events, as defined in section 1.1, be collected/recorded?
►IF NO, what criteria will be used?
_____Only adverse events deemed related/possibly related to study
_____Only adverse events that are deemed serious
_____Only adverse events that are deemed related AND serious
_____Other: specify:
3.2 How will adverse event data be collected/recorded? Check all that apply
_____Paper AE forms/source documents
_____Spreadsheet (paper or electronic)
_____Database specify name/type of database(s):
3.3. How will AEs be classified/graded? Check all that apply
_____World Health Organization Criteria (WHO)
_____NCI Common Toxicity Criteria, Version 2.0/ NCI Common Terminology Criteria,
Version 3.0
_____NCI CTCAE Version 4.0
_____Mild/Moderate/Severe
____Serious/Not serious
_____Other: specify
3.4 What scale will the PI use when evaluating the relatedness of adverse events to
the study participation? Check all that apply.
_____The PI will determine the relationship of adverse events to the study
using the following scale:
Related:
Possibly related:
Unrelated:
AE is clearly related to the intervention
AE may be related to the intervention
AE is clearly not related to intervention
_____The PI will use an alternative attribution scale. specify
3.5 When will recording/reporting of adverse events/unanticipated problems begin?
_____After subject signs consent
____________________________________________________________________________________________
35
_____After subject begins study drug/ device placement/intervention /study-related
procedure/specimen collection
_____Other: specify
3.6 When will the recording/reporting of adverse events/unanticipated problems end?
_____End of study drug/device/intervention/participation
_____30 days post study drug/device/intervention
_____Subject completes intervention and follow up period of protocol
_____Other: specify
3.7 How will Adverse Events, Unanticipated Problems, Protocol Violations be
reported? Complete the table below to answer this question
Type of Event
To whom will
it be reported:
Any internal event resulting IRB
in death that is deemed
DEFINITELY related to
(caused by) study
participation
Internal, Serious,
IRB
Unexpected adverse event
TIP: if you answered NO
to question3.1- modify
this section to include only
those AE’s you plan to
record. ( example: if you
are recording only those
that are related/ possibly
related- state “ Internal,
Serious, Related or
Possibly Related,
Unexpected adverse
events.
Delete this row if the
IRB
study does not involve a
device.
For Device Studies:
Unanticipated adverse
device effects (internal)
Unanticipated Problems
IRB
that are not adverse
Time Frame for
Reporting
Within 24 hours
How reported?
Within 7 calendar
days from the time
the study team
received
knowledge of the
event.
AE Reporting Form
See Appendix
Phone call and case report
form
Timeline includes
submission of
signed hardcopy of
AE form.
Within 10 day
calendar days of
the study team
receiving
knowledge of the
event
Within 7 calendar
days from the time
ADE Reporting Form
See Appendix
Unanticipated Problem report
form.
____________________________________________________________________________________________
36
events or protocol
violations
Protocol Violations
IRB
the study team
received
knowledge of the
event.
Within 7 calendar
days from the time
the study team
received
knowledge of the
event.
See Appendix
Protocol Violation and
Enrollment Exception
Reporting Form
See Appendix
OUTSIDE SPONSOR
All Serious adverse events Sponsor
TIP: if you answered NO
to question3.1- modify
this section to include
only those AE’s you plan
to record. ( example: if
you are recording only
those that are related/
possibly related- state “
Serious, Related or
Possibly Related adverse
events.
Internal Serious and
Sponsor
Unexpected
adverse event resulting in
change to the protocol or
consent..
Delete this row if the
Sponsor
study does not involve a
device.
For Device Studies:
Unanticipated adverse
device effects (internal)
Unanticipated Problem
Sponsor
Insert time frame
to report to
sponsor
Insert name of form and
method of reporting to the
sponsor
Within 7 calendar
days from the time
the study team
received
knowledge of the
event.
Timeline includes
submission of
signed hardcopy of
AE form
Within 10 day of
the study team
receiving
knowledge of the
event
Insert name of form and
method of reporting to the
sponsor
Insert required
timeframe.
If there is no
Insert reporting method
Insert reporting method
____________________________________________________________________________________________
37
Protocol violations
Sponsor
information from
the sponsor use
the same time
frames as abovein reporting
External, serious
and unexpected
AE resulting in
Change to the
protocol or
consent to the
IRB.
Insert required
timeframe
Insert reporting method
Delete the section below if the study does not involve an independent DSMB/DSMC
IF YOU REFERENCE THE SPONSORS PROTOCOL IN THE TABLE BELOW MAKE
SURE THE SECTION IN THE SPONSORS PROTOCOL ADEQUATELY ANSWERS
THE QUESTIONS
INDEPENDENT DSMB/DSMC
Insert what items the
DSMB/DSMC wants to
Review (AEs, SAEs,
early withdrawals, etc)
Unanticipated Problem
DSMB/DSMC
Insert reporting
method
Insert reporting method
DSMB/DSMC
Insert reporting method
DSMB/DSMC Reports
IRB
Insert required
timeframe
15 calendar days of
the study team
receiving the report

Copy of DSMB/ DSMC report
Delete the section below if the study does not involve an IND/IDE in which a UVa
faculty member is the PI of the IND/IDE.
UVa PI HELD IND/IDE
Life-threatening and/or
FDA
fatal unexpected events
related or possibly related
to the use of the
investigational agent.
Serious, unexpected and FDA
related or possibly related
adverse events
Delete this row if the
FDA
study does not involve a
device
For Device Studies:
Within 7 calendar
days of the study
team learning of
the event
Form FDA 3500A
(MedWatch) or narrative
Within 15 calendar
days after the study
team receives
knowledge of the
event
Within 10 working
days of the study
team receiving
knowledge of the
event
Form FDA 3500A
(MedWatch) or narrative
Form FDA 3500A
(MedWatch) or narrative
____________________________________________________________________________________________
38
Unanticipated adverse
device effects (internal or
external)
All adverse events
FDA
Annually
IND annual report

Delete the section below if a UVA PI is not the overall PI of the multi-site trial and
or the multi site study does not involve an IND/IDE held by the UVa faculty member.

IF YOU REFERENCE THE SPONSORS PROTOCOL MAKE SURE THE
SECTION IN THE SPONSORS PROTOCOL ADEQUATELY ANSWERS THE
QUESTIONS IN THE TABLE BELOW

The IRB-HSR strongly encourages PIs that are also holding their own IND/IDE to utilize
the IRB-HSR IRB online adverse events database for RECORDING all adverse events. The
principal investigator can then use this database to produce a report of all adverse events on
the study to do an aggregate review, which is helpful since an annual report to the FDA
containing this information is required by the FDA.
If the Cancer Center Protocol and Review Committee (PRC) will review this protocol
additional reporting requirements are found in the PRC section of this protocol.
UVA PI of MULTI-SITE TRIAL
Serious, unexpected and All Research
related or possibly
Sites
related adverse events
Within 15 days
after the Overall PI
receives knowledge
of the event.
IND/IDE Safety Report
(Cover letter, copy of
MedWatch/narrative)
Delete this row if the
All Research
study does not involve Sites
a device.
For Device Studies:
Unanticipated adverse
device effects (internal or
external)
Unanticipated Problem
All Research
Sites
Within 15 calendar
days from the time
the Overall PI
receives knowledge
of the event.
Letter to Participating PIs,
Copy of MedWatch or
narrative
Within 15 calendar
days from the time
the Overall PI
receives knowledge
of the event.
Letter to Participating PIs,
Copy of MedWatch or
narrative
4. How will the endpoint data be collected/recorded. Check all that apply
_____Protocol specific case report forms
_____Source documents
_____Database: specify
_____Other: specify
5. Data and Safety Oversight Responsibility
5.1. Who is responsible for overseeing safety data for this study ?
e.g. Who is looking at data in aggregate form to identify trends?
____________________________________________________________________________________________
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Check all that apply
_____No additional oversight body other than the overall PI at UVa (skip question 5.2)
_____Medical Monitor This could include such things as the overall PI of a multisite
trial
_____DSMB/ DSMC- If your study is NIH funded, check with the center to determine
if they require a DSMB for this study.
_____Research Monitor: Insert Name ____________________________
Required for protocols funded by the Department of Defense
_____Other: specify ________________
5.2. What is the composition of the reviewing body and how is it affiliated with the
sponsor?
Members of the study team may NOT also be members of the DMSB.
5.3. What items will be included in the aggregate review conducted by the PI?
Check all that apply.
_____NA- PI is not the overall person overseeing the safety data for this study.
_____All adverse events
_____Unanticipated Problems
_____Protocol violations
_____Audit results
_____Application of dose finding escalation/de-escalation rules These should be
outlined under 2.4.
_____Application of study designed stopping/decision rules
_____Early withdrawals
_____Whether the study accrual pattern warrants continuation/action
_____Endpoint data
_____Other: (specify) ______
5.4 How often will aggregate review occur?
For additional information on aggregate review see:
www.virginia.edu/vpr/irb/hsr/continuations.html#aggreview
_____NA- PI is not the overall person overseeing the safety data for this study.
_____Annually
____________________________________________________________________________________________
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_____Monthly
_____Other: specify
5.5. How often will a report, regarding the outcome of the review by the
DSMB/DSMC, be sent to the sites?
_____ NA- there is no DSMB/ DSMC overseeing this study
_____Every six months
_____Once a year
_____Other: specify
5.6. How will a report of the information discussed in question 5.4 OR 5.5 be
submitted to the IRB?
_____Part of continuation status report
_____Separate report from DSMB/DSMC
_____Other: specify
____________________________________________________________________________________________
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